Many oncologists believe that ligand-targeted drugs will revolutionize cancer chemotherapy; however there are few ligands that can target to a single tumor type let alone a variety of tumors. We showed that hyaluronan oligosaccharides covalently attached to the surface of a liposome (HAL) bind to and internalize in CD44 expressing cancer cell lines. This is an important accomplishment because CD44 is over-expressed on the surface of many human tumors including: breast, prostate, colon, lung, ovarian, melanoma and brain; hence HAL could be a cancer targeting ligand for many tumor types. Our objective in the renewal is to use computer-aided ligand design to guide the synthesis of an improved lipid-linked ligand to CD44 for use in HAL. We propose to optimize the delivery properties of single drugs encapsulated in HAL to CD44-expressing tumors and to better delineate the toxicities to normal tissues. The drugs to be incorporated include: doxorubicin, SN38, cis-platinum and fluoroortic acid. We will investigate the hypothesis that anti-tumor activity of individual drugs, encapsulated in optimized HAL are superior to non-targeted liposome therapy in CD44 expressing murine and human tumors in mice. We will test the hypothesis that appropriate combinations of two drugs delivered in the same HAL can act in an additive or synergistic fashion to provide superior cytotoxicity than either drug alone against CD44 expressing cancer cells in culture. Drug combinations to be studied include: doxorubicin & SN38; doxorubicin & cis-platinum; cis-platinum & SN38; SN38 & fluoroortic acid and fluoroortic acid & folinic acid. To achieve this latter goal we will develop novel lipids that can assemble into liposomes and provide better drug retention for combinations of drugs. We will incorporate ortho ester lipids that hydrolyze at low pH into the liposomes to provide triggered release of drug combinations at the target. Finally, we will examine the hypothesis that anti-tumor activity of these drug combinations, encapsulated in optimized HAL are superior to non-targeted liposome therapy in CD44 expressing murine and human tumors in mice. Success in this research will provide new ligands for targeting CD44 expressing tumors, new lipids for formulating liposomes with better drug retention and release characteristics, and most importantly should enable targeted chemotherapy for a broad spectrum of human cancers of epithelial origin.